The invention relates to methods of orally administering epothilones to a patient in a manner that increases bioavailablity. The invention further relates to pharmaceutical compositions, pharmaceutical dosage forms, and kits for use in the methods of the invention. In particular, the invention relates to a solid oral dosage form of an epothilone.
Epothilones are 16 member cyclic macrolide molecules which find utility in the pharmaceutical field. For example, Epothilone A and B are naturally occurring compounds that can be isolated from certain microorganisms; these two compounds have the following structures: 
Since the introduction of epothilones into the art, many groups have been designing, synthesizing and testing analogs of the naturally occurring epothilones in an attempt to develop useful pharmaceuticals. (See, e.g., D. Schinzer et al., Angew. Chem. Int. Ed. Engl., 1997, 36, No. 3, 523-524; K. C. Nicolaou, et al., J. Amer. Chem. Soc., 1997, 119, 7974-7991; K. C. Nicaloau et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 20, 2399-2401; A. Balog et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 23/24, 2801-2803).
Known epothilones exert microtubule-stabilizing effects similar to Taxol(copyright) and therefore exhibit cytotoxic activity against rapidly proliferating cells, such as occur in cancer and other hyperproliferative cellular diseases (See Angew. Chem. Int. Ed. Engl., Vol. 35, No. 13/14, 1996 and D. M. Bollag, Exp. Opin. Invest. Drugs, 6(7): 867-873, 1997).
Before epothilones can be used to treat diseases in patients, however, they must be formulated into a pharmaceutical composition that can be administered to the patient; for example, into a dosage form suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraaterial), or transdermal administration. Formulations for oral administration are particularly preferred since they are more convenient and easier to administer than other formulations. Also, the oral route of administration avoids the pain and discomfort of parenteral administration. Accordingly, formulations for oral administration are preferred by patients and result in better patient compliance with dosing schedules.
The usefulness of an oral formulation, however, requires that the active agent be bioavailable. Bioavailability of orally administered drugs is affected by various factors including, for example, drug absorption throughout the gastrointestinal tract, stability of the drug in the gastrointestinal tract, and the first pass effect. Thus, effective oral delivery of an active agent requires that the active agent have sufficient stability in the stomach and intestinal lumen to pass through the intestinal wall. Many drugs, however, tend to degrade quickly in the intestinal tract or have poor absorption in the intestinal tract so that oral administration is not an effective method for administering the drug.
Pharmaceutical compositions intended for oral administration are typically solid dosage forms (e.g., tablets) or liquid preparations (e.g., solutions, suspensions, or elixirs). Solid dosage forms, however, can impose restrictions on the pharmaceutical use of the active agent since some patient populations have difficulty, either physical or psychological, in swallowing solid oral dosage forms. If a liquid dosage form is available, these patients could more easily take the required dose of active ingredient by having it administered in the form of an oral liquid preparation that they can drink or having it administered, for example, by a naso-gastric tube. Thus, liquid oral dosage forms are desirable.
Liquid oral pharmaceutical compositions require a suitable solvent or carrier system to dissolve or disperse the active agent to enable the composition to be administered to a patient The solvent system must be compatible with the active agent and be non-toxic to the patient Commonly, the solvent for liquid oral formulations is a water based solvent.
The formulation of certain epothilones presents difficulties in addition to the normal hurdles, in that certain epothilones are either or both acid labile and/or poorly soluble in aqueous media, which is the media of first choice for oral solutions. The present invention, however, overcomes these difficulties and provides methods and pharmaceutical formulations for the oral administration of epothilones wherein the epothilones are sufficiently bioavailable to have a pharmacological effect.
The present invention encompasses a method of orally delivering epothilones to a mammal while reducing or avoiding the degradation, decomposition, or deactivation of the epothilone by the gastrointestinal system, particularly by gastric fluid in the stomach. In one embodiment, the method encompasses administering the epothilone in, or with, a pharmaceutically acceptable acid neutralizing buffer. In a preferred embodiment, the administration comprises the use of two solutions, one comprising the active epothilone alone, or in a pharmaceutically acceptable carrier, and the other comprising the pharmaceutically acceptable neutralizing buffer.
The invention therefore includes pharmaceutical compositions comprising an epothilone either in a solid form which is suitable for constitution, or reconstitution if lyophilized, into a pharmaceutically acceptable solution or as a pre-made solution. The invention also encompasses pharmaceutical compositions comprising a pharmaceutically acceptable neutralizing buffer either in solid form suitable for constitution, or reconstitution if lyophilized, into a pharmaceutically acceptable solution or as a pre-made solution.
In a more specific embodiment, the present invention is directed to methods of increasing the bioavailability of an orally administered epothilone. The methods involve orally administering one or more epothilones of Formula: 
wherein:
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, 
W is O or NR16;
X is O; S; CHR17; or H, R18;
Y is selected from the group consisting of O; H, H; H, OR22; OR23, OR23; NOR24; H, NOR25; H, HNR26R27; NHNR28R29; H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal;
B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41;
D is selected from the group consisting of NR42R43 or heterocyclo;
R1, R2, R3, R4, and R5 are selected from H, lower alkyl;
R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
R17, R18, R22, and R23 are selected from the group consisting of H, alkyl, and substituted alkyl;
R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl;
R12, R16, R27, R29, R31, R38, and R43, are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51Cxe2x95x90O, R52OCxe2x95x90O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate or prodrug thereof; and orally administering one or more pharmaceutically acceptable acid neutralizing buffers.
The pharmaceutically acceptable acid neutralizing buffer may be administered concurrently with, before, after, or both before and after administration of the one or more epothilones of interest. When administered before the active epothilone, the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before the epothilone is administered. When administered after, the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour after the epothilone is administered.
The pharmaceutically acceptable acid neutralizing buffer solution, which may be a liquid formulation and which may be constituted immediately prior to administration, comprises one or more components that are capable of neutralizing acidic solutions, particularly gastric fluid, for a period of time. The buffer components include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. Preferably, the buffer components are water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, hydrochloric acid, sulfuric acid, glutamic acid, and salts thereof.
The pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to neutralize gastric fluids in the stomach and increase the amount of the epothilone that is absorbed by the gastrointestinal system. The pharmaceutically acceptable acid neutralizing buffer may be administered as an aqueous solution having a pH of between about 5 to 9. The pharmaceutically acceptable acid neutralizing buffer may be administered as an aqueous solution of anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.
The present invention increases the bioavailability of the orally administered epothilone significantly above that of an epothilone orally administered without a neutralizing buffer. In one embodiment the bioavailability of the one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is at least 20 percent. The one or more epothilones or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof may be orally administered as a solution in propylene glycol and ethanol, for example, wherein the ratio of propylene glycol:ethanol is about 80:20.
A preferred epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.
The invention also encompasses kits which comprise the desired epothilone and a soluble buffer composition. The invention encompasses a kit comprising (a) a pharmaceutical composition comprising an epothilone which is suitable for oral administration and (b) a pharmaceutical composition comprising an acid neutralizing buffer which is suitable for oral administration.
In one embodiment the kits include:
(i) a first component comprising one or more epothilones of Formula: 
xe2x80x83wherein G, W, X, Y, B1, B2, D, R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R16, R17, R18, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 R51, R52, R53, and R61 are defined above; and
(ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer,
wherein the first component and the second component are provided as a liquid oral dosage form or as a solid pharmaceutical composition that can be constituted or reconstituted with a solvent to provide a liquid oral dosage.
The pharmaceutical composition to be reconstituted with a solvent may be provided as a tablet. The first component or the second component may be anhydrous. The kit may optionally include solvents for reconstituting the first or second components. The solvent for reconstituting the first component may be a mixture of propylene glycol and ethanol, wherein the ratio of propylene glycol:ethanol is about 80:20.
The invention is further directed to a pharmaceutical composition comprising:
(i) one or more epothilones of Formula: 
xe2x80x83wherein G, W, X, Y, B1, B2, D, R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, R16, R17, R18, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43R51, R52, R53, and R61 are defined above, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof in solid form; and
(ii) a solid pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more epothilones, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof when the pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form.